• Must be competent and able to comprehend, sign, and date an Institutional Review Board (IRB) approved ICF before performance of any study-specific procedures or tests.

• Men or women ≥18 years old.

• Pathologically documented breast cancer that:

∙ Is unresectable or metastatic.

‣ Has always been HER2-IHC 0 and never previously HER2-positive (IHC 3+ or ISH+) or HER2-low (1+, or 2+ ISH-) on prior pathology testing according to American Society of Clinical Oncology College of American Pathologists (ASCO-CAP) guidelines.

‣ Is either HR-positive or HR-negative per ASCO-CAP guidelines

‣ If HR-positive, has or has not been treated with a CDK4/6 inhibitor.

‣ Has been treated with 1 or 2 prior lines of systemic therapy (which includes either standard cytotoxic chemotherapy and/or antibody-drug conjugates \[e.g sacituzumab-govitecan, datopotamab-deruxtecan, or others\]) in the metastatic setting. If recurrence occurred within 6 months of the last dose of (neo)adjuvant chemotherapy, (neo)adjuvant chemotherapy would count as 1 line of therapy. Endocrine therapies, immune checkpoint inhibition without systemic chemotherapy, and targeted-therapies (e.g. olaparib, or others) do not count as systemic cytotoxic chemotherapy lines and are unlimited prior to enrolment.

‣ Was never previously treated with anti-HER2 therapy.

• Documented radiologic progression (during or after most recent treatment).

• Adequate archival tumor sample \<3 years-old available for assessment of HER2 status by IHC and by HS-HER2 quantitative assay. If archival tissue is not available or inadequate for assessment (e.g. decalcified bone, cytology, or other), a newly obtained biopsy from a metastatic site (or breast tissue if locally advanced/unresectable disease as the only site of advanced disease) is required on enrolment.

• Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1

• ECOG PS 0 or 1.

• Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to C1D1.

• Adequate bone marrow function within 28 days before C1D1, defined as:

‣ Platelet count ≥100,000/mm3 (Platelet transfusion is not allowed within 1 week prior to Screening assessment)

⁃ Hemoglobin level ≥9.0 g/dL (red blood cell transfusion is not allowed within 1 week prior to Screening assessment)

⁃ Absolute neutrophil count ≥1500/mm3 (granulocyte colony-stimulating factor administration is not allowed within 1 week prior to Screening assessment)

⁃ Adequate renal function within 28 days before C1D1, defined as:

⁃ \- Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault Equation.

⁃ Adequate hepatic function (Table 1) within 28 days before C1D1, defined as:

∙ Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3×ULN (\< 5×ULN in participants with liver metastases)

‣ Total bilirubin ≤1.5 × ULN if no liver metastases or \<3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline

⁃ Adequate blood clotting function within 28 days before C1D1, defined as:

⁃ \- International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN

⁃ Adequate treatment washout period before C1D1, defined as:

∙ Major surgery, minimum washout period ≥ 4 weeks

‣ Radiation Therapy including palliative stereotactic radiation therapy to chest, minimum washout period ≥ 4 weeks

‣ Palliative stereotactic radiation therapy to other anatomic areas including whole brain radiation, minimum washout period ≥ 2 weeks

‣ Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\], hormonal therapy, antibody-based therapy, or retinoid therapy, minimum washout period ≥ 3 weeks

‣ Targeted agents and small molecules, minimum washout period ≥ 2 weeks or 5 half-lives, whichever is longer

‣ Cell-free and Concentrated Ascites Reinfusion Therapy (CART), peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion, minimum washout period ≥2 weeks prior to screening assessment

⁃ Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of T-DXd. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.

⁃ Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening (those using hormonal methods must have been stable on their chosen form of contraception for 3 months prior to study entry) and must agree to continue using such precautions for 7 months after the last dose of T-DXd. Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of T-DXd. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.

⁃ Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom from screening to 4 months after the final dose of T-DXd. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period, as described in Table 3. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of enrolment, throughout the study and for 4 months after the last dose of T-DXd. Preservation of sperm should be considered prior to enrolment in this study.

⁃ Female subjects must not donate, or retrieve for their own use, ova from the time of enrolment and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrolment in this study.